Unveiling the Significance of the ‘Bathtub’ Shape in Blood Glucose Curve Analysis

Abstract

Despite extensive research on insulin usage in diabetes, an effective method for regulating insulin dosage and timing has not emerged. Self-monitoring of blood glucose (SMBG) is crucial for diabetes self-care, but its utility is limited in intense insulin treatments. Moreover, persistent nighttime hypoglycaemia anxiety and neuropathic gastric issues pose significant challenges for patients with elevated nocturnal blood sugar and frequent post-meal hypoglycaemia. The “bathtub” curve outlines a daily glucose profile where levels spike after dinner, normalizing only after morning correction. This chapter focuses on addressing the difficulties posed by this glucose pattern for healthcare providers and researchers. The insights offered here could prove invaluable for diabetes management, potentially mitigating associated complications.

1. Introduction

Type 1 diabetes is a complex autoimmune disease characterized by the destruction of insulin-producing β-cells in the pancreas [1, 2]. This condition results in α-cell dysfunction, leading to reduced glucagon secretion during hypoglycemia. The delicate balance of blood glucose levels is maintained by a dynamic interplay of various factors, including insulin, glucagon, cortisol, adrenaline, and growth hormone [3]. Additionally, external factors such as stress, certain immunological processes, carbohydrate intake, and gluconeogenesis contribute to fluctuations in blood glucose levels. Furthermore, the role of weight management in influencing insulin action cannot be understated [4]. In this complex landscape of diabetes management, Self-Monitoring of Blood Glucose (SMBG) emerges as a crucial tool. SMBG provides immediate feedback on blood glucose levels, allowing individuals to make informed decisions about their insulin dosages, dietary choices, and physical activity. Regular SMBG, combined with appropriate adjustments in insulin therapy, diet, and lifestyle, can lead to improved long-term glycemic control, as reflected in lower hemoglobin A1c (HbA1c) levels [5]. Beyond these advantages, SMBG empowers individuals with type 1 diabetes to take an active role in their self-care and fosters a deeper understanding of how various factors affect blood glucose levels.

The regulation of glucose homeostasis is a multifaceted process influenced by circadian rhythms, which affect insulin sensitivity throughout the day [6]. Moreover, physical activity and the body’s natural insulin secretion also play significant roles in lowering blood glucose levels [7]. Given the potential for insulin to induce acute severe hypoglycemia and the cardiovascular complications associated with elevated blood glucose, there is a paramount need to strive for “near normoglycemia.”

Managing type 1 diabetes is an intricate and ongoing challenge, necessitating a continuous balancing act [5, 8, 9, 10]. To address these complexities and improve patient outcomes, individuals with type 1 diabetes must learn to manipulate many of these factors. This manipulation often involves the application of external subcutaneous insulin and diligent self-monitoring of blood glucose levels. Therefore, understanding the intricate web of factors that influence glucose homeostasis is essential for effective diabetes management. In this context, this article aims to delve deeper into the multifaceted nature of type 1 diabetes, shedding light on the various factors involved and the challenges faced by those living with the condition.

2. Clinical insights and observations

In 2022, we were motivated to publish a case report pertaining to this chapter, where we provided an in-depth analysis of the details. In the discussion section, we delve further into the specifics of our findings [11].

Since the pancreas transplant rejection [12], the patient has benefited from continuous subcutaneous glucose monitoring with programmable alarm thresholds, which trigger pre-emptive alerts for decreasing or increasing blood sugar levels. However, persistent nocturnal hypoglycaemic anxiety and neuropathic-induced gastric paresis remained significant challenges. These were associated with elevated nocturnal blood sugar levels and frequent postprandial hypoglycaemic episodes. Hypoglycaemic events lead to high blood sugar levels hours later due to excessive carbohydrate intake and prolonged counter-regulatory responses of insulin antagonists such as adrenaline, cortisol, glucagon, and growth hormone. Prolonged type 1 diabetes can disrupt this counter-regulation, often resulting in a lack of surge in adrenaline and glucagon during hypoglycaemia. Hypoglycaemia significantly contributes to the development of long-term complications in type 1 diabetes patients, particularly through excessive carbohydrate consumption following hypoglycaemic episodes [13]. In our previous publication [11] related to the mentioned patient, this occasionally led to the paradoxical situation where reducing insulin resulted in partial improvement of HbA1c levels.

The so-called “bathtub” curve describes a blood glucose daily profile in which blood sugar levels rise after dinner and only return to the target range after waking up in the morning [14]. The primary cause of such a pattern is the challenging-to-treat nocturnal hypoglycaemic anxiety experienced by patients. After dinner, blood sugar is intentionally kept above the target range, achieved either by administering less prandial insulin than necessary or by consuming a small snack before sleep. The goal is to avoid nocturnal hypoglycaemia, to which one is vulnerable while asleep. Hypoglycaemic anxiety is common in type 1 diabetes and plays a significant role in patients whose blood sugar levels are not satisfactorily manageable [15].

To address this issue, particularly in the first years following diagnosis until sufficient experience in everyday insulin management is gained, special attention should be given to avoiding severe hypoglycaemic episodes. To prevent this situation, diabetologists generally set slightly higher target blood sugar levels during the initial phase of insulin therapy. Once hypoglycaemic anxiety develops, it becomes challenging to treat, often persisting throughout the patients’ lives. This is particularly concerning, given that the night constitutes about one-third of one’s lifetime and contributes significantly to the development of complications.

In this scenario, prolonged inadequate blood sugar control with correspondingly high HbA1c levels led to neuropathic gastric paresis. This condition further contributes to the “bathtub” shape of the blood glucose daily profile, as food, and consequently the ingested carbohydrates, remain in the stomach for a longer duration. They are only gradually passed from the stomach to the intestines for absorption, primarily occurring in the evening. For the patient, this resulted in a delayed increase in blood sugar levels, often occurring many hours after a meal. Consequently, the gastric paresis led to early postprandial hypoglycaemic episodes due to rapidly acting insulin shortly after eating. This exacerbates daytime hypoglycaemic issues and is further intensified by attempts to compensate for intentionally elevated nighttime blood sugar levels by maintaining values near the hypoglycaemic threshold during the day.

In terms of differential diagnosis, changes in insulin requirements and consequent additional blood glucose fluctuations must also consider conditions such as thyroid dysfunction (generally yielding slightly higher blood glucose levels), adrenal insufficiency (reduced insulin requirement, leading to hypoglycaemia primarily at night), or celiac disease (carbohydrate malabsorption). All these disorders occur within the context of a polyglandular autoimmune syndrome, with a lifetime prevalence of approximately 15–30%, more frequently observed in type 1 diabetes mellitus [16]. Throughout the years of care, these conditions were repeatedly ruled out in the patient’s case.

The patient’s blood glucose trajectory is depicted in Figure 1. The dose of basal insulin should primarily be determined based on the metabolism of glucose, which mainly originates from liver production during the night. On the other hand, rapid-acting insulin should be adjusted mainly according to the quantity of orally ingested carbohydrates during the daytime. Since usually no food is consumed at night, having an identical blood glucose level at “bedtime” (blood glucose measured just before sleeping) and in the morning upon waking indicates that basal insulin was appropriately dosed for the night, regardless of whether both values are high or normal. This is also reflected in a bathtub curve. Therefore, comparing “bedtime” blood glucose to morning levels is a crucial aspect in evaluating blood glucose profiles.

Figure 1.

Nocturnal blood glucose (BG) profile: differential diagnosis: high BG in the morning with normal BG before bedtime. The curve represents average values at the same times of day over a fixed period. 1. Insufficient basal insulin during the night; 2. Dawn phenomenon (marked circadian rhythm with an early-morning rise in BG); 3. Excessive glucose intake after hypoglycemia.

A nearly physiological ratio of basal insulin to total insulin ranging from 30 to 50% is also indicative of optimal basal insulin dosing. Often, individuals with type 1 diabetes themselves limit their daily carbohydrate intake to reduce the dose of rapid-acting insulin, consequently increasing the percentage of basal insulin (as was the case with the described patient, reaching 60%).

Sometimes, it can be challenging to estimate the appropriate proportion of basal insulin, especially when rapid-acting correction insulin (as a replacement for basal insulin) is used for higher blood glucose levels regardless of meals. A so-called “meal omission test” can be helpful: if blood glucose remains stable during the test, it can be assumed that the basal rate is set correctly. In the case of the described patient, who regularly conducted such tests, the basal rate was usually set accurately.

When the “bedtime” blood glucose is within the target range, but the morning blood glucose is elevated, three classic differential diagnoses should be considered (Figure 2). These differential diagnoses can be distinguished through an analysis of the overnight blood glucose measurements:

1. Excessive carbohydrate intake after nocturnal hypoglycaemia. The previously described Somogyi effect, which explained a counter-regulatory response with elevated morning blood glucose following nighttime hypoglycaemia, can lead to a similar profile. However, this effect is currently considered scientifically questionable to non-existent and is deemed highly unlikely due to the impaired adrenergic counter-regulation in long-standing type 1 diabetes. More often, the cause is excessive carbohydrate intake [17].

2. Insufficient basal insulin to cover hepatic glucose output during the night: continuous rise in blood glucose from the “bedtime” measurement until early morning; subsequently, regular elevated blood glucose levels in the morning, if the liver’s glycogen reservoir was sufficiently replenished with carbohydrates consumed orally during the day.

3. Dawn or sunrise phenomenon [18]: blood glucose level around 3 AM is identical to the “bedtime” reading; then there is a subsequent increase in blood glucose levels towards the morning; this can be explained by the circadian rhythm of endogenous insulin antagonists (such as adrenaline, growth hormone, glucagon, and cortisol).

   Throughout the diabetes journey, such patients intentionally used insufficient basal insulin despite having hypoglycemic anxiety, even though their blood glucose levels were within the “bedtime” target range. A pronounced dawn phenomenon, which can also occur due to an innate circadian rhythm variation, was not present.

   Other reasons that contributed to increased blood glucose fluctuations and accentuated the risk of nocturnal hypoglycemia during the course of the patient’s diabetes journey were:

Figure 2.

Typical blood glucose daily profiles: model theoretical representation. Explanation and most common causes, see Table 1. Adapted from Fetian et al. [11].

Theoretical model representation, see Figure 2.

Under the immunosuppressive corticosteroid therapy following the pancreas transplant, daytime blood glucose levels increased due to the stimulation of gluconeogenesis in the liver. Consequently, this led to nocturnal hypoglycemia as a result of the liver’s depleted glucose reservoir.

1. The developing renal insufficiency necessitated a gradual reduction in insulin dosage for the patient due to the diminished breakdown of insulin, which occurs to about one-third through renal pathways.

2. In addition to the mentioned “bathtub curve,” there are various other blood glucose daily profile patterns well-known to diabetologists, such as the peak, valley, hill, sky, or erratic (unpredictable) blood glucose curve. In Figure 2 and Table 1, the manifestation and causes of these daily profiles are theoretically summarized. Over the course of her illness, the patient experienced each of these characteristic curve patterns repeatedly.

Name of the theoretical model of the blood glucose curve	Description of blood glucose	Most common causes of blood glucose curves in type 1 diabetes with 3 main meals and basal/bolus insulin
Peak	Increasing over the day, decreasing at night	Excessive basal insulin at night, carbohydrate/insulin imbalance during all meals throughout the day
Sky	All blood glucose values high	Insufficient daytime insulin, as there is no overnight rise in blood glucose levels, the basal insulin is at least sufficient during the night
Valley	Decreasing over the day and gradually increasing over the night	Insufficient basal insulin at night, morning bolus insulin for not yet optimally achieved postprandial target values
Hill	Short-term blood glucose increase	Inadequate bolus insulin relative to carbohydrates during a meal
Bathtub	Higher at night compared to daytime.	Carbohydrate/insulin imbalance during dinner
Erratic	Unpredictable, constantly changing blood glucose values (blue day 1/yellow day 2)	Insulin-carbohydrate ratio rarely adjusted or lipodystrophies causing irregular subcutaneous insulin absorption or lack of adjustment for intense physical activity

Table 1.

Explanation and most common causes for typical blood glucose daily profiles.

The long-term care of patients with type 1 diabetes requires a significant amount of experience and interdisciplinary collaboration. Patients with type 1 diabetes frequently encounter new situations that demand flexible and differentiated responses. In addition to well-established and often non-textbook knowledge (such as the reasons leading to typical blood glucose daily profiles, often conveyed by experienced diabetologists), patients should also be continuously offered the latest technological aids.

The presented case illustration depicted an extreme course of type 1 diabetes, through which many situations that diabetologists regularly encounter were described. When patients receive appropriate training from the outset of type 1 diabetes diagnosis, they often have a good chance of managing the condition effectively in their daily lives. This can help maintain their quality of life and significantly reduce the risk of a shortened lifespan [11]. Overall, such dramatic courses, involving nearly all conceivable complications as in the present case, remain exceptions.

The patient demonstrated remarkable perseverance, never giving up and continuously striving to manage her “brittle diabetes.”

3. Conclusion

Type 1 diabetes patients experience a wide array of blood glucose profiles throughout the course of their illness. The underlying causes are often ambiguous and diverse, influenced by factors such as dietary habits, physical activity, improper handling of technology, side effects of insulin therapy or other treatments, comorbidities, and stress. Occasionally, blood glucose profiles can be quite suggestive, as seen in intentionally accepted high nighttime blood glucose levels due to hypoglycemic fear, resulting in a “bathtub curve” (elevated blood glucose in the morning and at “bedtime,” but normal during the day). The assessment of blood glucose profiles is central to the education and care of patients with type 1 diabetes.

The case demonstrates that even experienced diabetologists find that the existing tools of insulin therapy might not suffice to avoid such blood glucose daily profiles. However, it is hopeful that the planned “semi-closed-loop” insulin therapy for the patient will significantly improve blood glucose levels.

4. Summary

Blood glucose daily profiles of patients with diabetes are of paramount importance for better disease management and continue to pose a challenge for diabetologists. In the present case of a patient with long-standing type 1 diabetes and severe complications, a characteristic “bathtub” profile of the blood glucose curve is showcased. This specific pattern stems from the patient’s behavior driven by nocturnal hypoglycaemic fear. The patient intentionally allows her blood glucose to rise after dinner until the morning, only lowering the blood glucose levels after waking up the next morning. Through this example, differential diagnostic considerations for various commonly occurring blood glucose daily profile patterns are discussed.

Acknowledgments

I extend my sincere appreciation to Dr Lukas Villiger for his invaluable support in endocrinology and to my dedicated team at HAP MZB for their collaboration. I'm grateful to Prof. Josef Flammer whose passion for science and commitment to excellence have been a constant source of inspiring me.

I would like to acknowledge Healthbook Times for their collaboration, as the adapted figure was generously provided by H+O Communications Ltd., Zurich, Switzerland. Their contribution greatly enhanced the quality of this work.

I am deeply indebted to my beloved uncle, Dr. Issa Fitian, my brother Ashraf Fetian, my mother, my wife, my daughter, and the rest of my family for their unwavering encouragement and belief in my pursuits. Their support has been a pillar of strength throughout this endeavour.

Last but not least, I extend my deepest gratitude to Palestine, my homeland, and express profound respect for the spirits of the Palestinian community, particularly the courageous doctors whose inspiration drives our advancements in the field of medicine.

Funding

This work received no specific grant from any funding agency in the public, commercial, or non-profit sectors.

Conflicts of interest

The author declare that there are no commercial or financial relationships that could be construed as potential conflicts of interest.